Naphthyloxysalicylanilides

ABSTRACT

NEW NAPHTHYLOXY-SUBSTITUTED ANILIDES ARE DISCLOSED. THE COMPOUNDS ARE USEFUL GERMICIDAL AGENTS. PREFERRED COMPOUNDS CONTAIN HALOGEN SUBSTITUENTS.

United States Patent Oflice Patented Dec. 19, 1972 US. Cl. 260-559 S 9Claims ABSTRACT OF THE DISCLOSURE New naphthyloxy-substituted anilidesare disclosed. The compounds are useful germicidal agents. Preferredcompounds contain halogen substituents.

FIELD OF THE INVENTION The present invention relates to a new class ofbiologically active compounds.

BACKGROUND OF THE INVENTION The use of anilides as biocidal compounds iswell known. In particular, the use of phenoxy-substituted anilides iswell known. Thus the use of phenoxy-substituted halogenatedsalicylanilides as germicides is described in British Pat. No.1,108,393, and their use as germicides and anthelmintics is described inNetherlands patent application No. 6707849. Also, the use ofphenoxy-substituted carbanilides as germicides is described in J. Med.Chem., 1968, 11, 163, and their use as anti-coccidial agents isdescribed in Australian patent application No. 46,399/ 64.

SUMMARY OF THE INVENTION It has now been discovered that if an anilidecontains a naphthyloxy substituent said anilide is a surprisinglyeffective biocidal agent. Thus it has surprisingly been found thatpresence of the weighty naphthyloxy group instead of the comparativelylight phenoxy group gives comparable biocidal activity and in someinstances more favourable activity. This is particularly true if saidanilide is selected from the class of salicylanilides and carbanilides.It has been found that such naphthyloxy-substituted anilides showsurprising germicidal activity. Also, they can be used advantageously inconjunction with detergents.

The scope of the invention, therefore, includes anaphthyloxy-substituted anilide in which said anilide is selected fromthe class consisting of salicylanilides and carbanilides. Preferably thenaphthyloxy-substituent is in the aromatic ring of an aniline group insaid anilide, particularly in the 2, Le. ortho, position of saidaromatic ring.

Particularly preferred compounds of the invention arenaphthyloxy-substituted anilides in which said anilide is selected fromthe class consisting of halogen-substituted salicylanilides andcarbanilides. Other substituents can be present. Preferably the halogenis chlorine or bromine and preferably the anilide contains from 1 to 3halogen atoms.

Illustrative structural formulae are ll3r 6 B r 5 CO.NH 3

4,6,4'-tribromo-2-ot-naphthyloxy-salicyanilide Br ---Br 6 B r;@-NH. o 0.NHQ3

2,5 ,4',6'-tetrabromo-2'-a-naphthyloxycarbanilide An aspect of theinvention is a germicidal composition containing anaphthyloxy-substituted anilide according to the invention. A preferredaspect of the invention is a germicidal detergent composition containinga naphthyloxy-substituted anilide according to the invention. Thedetergent composition can be in any convenient form such as liquid,paste or hard-surface cleaner but preferably should be in the form of atoilet bar. Suitable formulations for germicidal detergent compositionsare given in standard textbooks, for example in Schwartz and Perry,Surface -Active Agents.

A naphthyloxy-substituted anilide according to the invention can be usedin conjunction with other germicides, such as3,4,4'-trichlorocarbanilide, 3,4,4'-tribromosalicylanilide,2,2-dihydroxy-3,5,6,3',5',6'-hexachlorodiphenylmethane and4,2,4'-trichloro-Z-hydroxy-diphenylether.

A further aspect of the invention is a pharmaceutical or veterinarycomposition containing a naphthyloxy-substituted anilide according tothe invention together with a pharmaceutically acceptable orveterinarily acceptable carrier.

The anilides according to the invention can be prepared by a variety ofmethods. For example, one method is the condensation of anaphthylamino-phenylether with a salicyclic acid, the ether and thesalicylic acid being prepared by standard methods. A salicylanilide isthereby obtained. When a halogenated salicylanilide according to theinvention is required, a halogenated naphthylamino-phenylether and/or ahalogenated salicylic acid can be used. An alternative method is thedirect halogenation of a naphthyloxy salicylanilide.

Another example of a method of preparing an anilide according to theinvention is by reaction of a naphthylamino-phenylether with an arylisocyanate, the ether and the isocyanate being prepared by standardmethods. A carbanilide is thereby obtained. As with the salicylanilides,halogenated compounds can be made by appropriate condensation or byhalogenation of a naphthyloxy carbanilide.

The following illustrates the preparation of intermediates that can beused in the preparation of anilides according to the invention:

(a) 2-nitrophenyl-fi-naphthylether 50 gms. (0.3 mole) of fl-naphthol and13.8 gms. (0.25 mole) of potassium hydroxide were dissolved in 50 mls.of absolute alcohol. The alcohol was then removed to leave the drypotassium salt, after which 30.4 gms. (0.2 mole) of o-chloronitrobenzenewere added and the mixture was heated at 140 C. for 2 hours. When cool,the mixture was extracted into chloroform and the extracts Washed with 2N sodium hydroxide and then with water. The extracts were dried overanhydrous sodium sulphate. Distillation of the residue from thechloroform extracts gave 16.0 gm. (30% of 2-nitrophenyl-8-naphthylether, B.P. 220-230 C. at 0.8-1.5 mms.

(b) 2-nitrophenyl-a-naphthylether 47.5 gms. (0.315 mole) of a-naphtholand 17.4 gms. (0.315 mole) of potassium hydroxide were dissolved in 50mls. of absolute alcohol. The alcohol was removed, 49.7 gms. (0.315mole) of o-chloronitrobenzene added in the cold and the mixture heatedat 140 C. for 2 hours. Working up the reaction product as in section (a)above gave, in addition to a small amount of recoveredo-chloronitrobenzene, B.P. 65-75 C. at 0.6 mms., 20.4 gms. (23.8%) of2-nitrophenyl-u-naphthylether, B.P. 195205 C. at 0.6 mm.

(c) 4-chloro-2-nitrophenyl-B-naphthylether 25 gms. (0.15 mole) ofB-naphthol and 6.9 gms. (0.125 mole) of potassium hydroxide weredissolved in 50 mls. of absolute alcohol. The alcohol was removed, 19.1gms. (0.1 mole) of 2,5-dichloronitrobenzene were added in the cold, andthe mixture then heated at 140 C. for 2 hours. Working up the reactionproduct as in section (a) above gave 12.0 gms. (23%) of4-chloro-2-nitrophenyl-fl-naphthylether, B.P. 220-235 C. at 1-2 mms.,M.P. 58-60" C. from alcohol.

(d) 2-aminophenyl-fl-naphthylether To a vigorously stirred refluxingsolution of 13 gms. of zinc dust, 25 mls. of water, 75 mls. of ethanoland 8 gms. of calcium chloride was added over a half hour period 5.0gms. (0.037 mole) of Z-nitrophenyl-p-naphthylether, and the mixture wasthen refluxed for a further 2 hours. The hot solution was then filteredto remove unreacted zinc. The filtrate on cooling gave 3.0 gms. (65%) of2-aminophenyl-B-naphthylether, M.P. 73 C.

(e) 2-aminophenyl-a-naphthylether To a stirred refluxing solution of 52gms. of zinc dust, 100 mls. of water, 300 mls. of ethanol and 32 gms. ofcalcium chloride was added over a half hour period 20 gms. (0.148 mole)of Z-nitrOphenyI-u-naphthylether, and the reaction mixture was stirredfor'a further two hours. The hot mixture was filtered to removeunreacted zinc, the filtrate diluted with water and extracted withchloroform. The chloroform extracts were dried over anhydrous sodiumsulphate. Distillation of the residue from the chloroform extracts gave16.8 gms. (89%) of 2- aminophenyl-a-naphthylether, B.P. 190200 C. at 2.5

mms.

(f) 4-chloro-2-aminophenyl-fl-naphthylether To a stirred refluxingsolution of 20 gms. of zinc dust, 150 mls. of ethanol, 50 mls. of waterand 10- gms. of calcium chloride was added over a half hour period, 5.0gms. of 4-chloro-2-nitrophenyl-fl-naphthylether, and the mixture wasrefluxed for a further 2 hours. The hot solution was filtered to removeunreacted zinc. The filtrate on cooling gave 3.5 gms. (77.8%) of pure4-chloro-2-aminophenyl-fl-naphthylether, M.P. 12l-3 C.

4 The following examples illustrate the preparation and biologicalactivity of salicylanilides and carbanilides of the invention.

EXAMPLE 1 5-chloro-2'-fl-naphthyloxysalicylanilide A solution of 2.0gms. (0.0084 mole) of Z-aminophenyl-fl-naphthylether, 1.45 gms. (0.0084mole) of 5- chlorosalicyclic acid and 0.5 ml. of phosphorus trichlorideM IC* 0. 1

EXAMPLE 2 2'-fi-naphthyloxysalicylanilide 1.0 gms. of2-aminophenyl-jS-naphthylether, 0.58 gm. (0.0042 mole) of salicylic acidand 0.25 ml. of phosphorus trichloride in 20 mls. of chlorobenzene wererefluxed for three hours. Working up the reaction product as describedin Example 1 gave 0.5 gm. (32%) of 2'19- naphthyloxysalicylanilide, M.P.1l8-120 C. from an alcohol-water mixture.

MIC l-2 EXAMPLE 3 2'-a-naphthyloxysalicylanilide 2.0 gms. (0.0084 mole)of 2-amiophenyl-a-naphthylether, 1.16 gms. (0.0084 mole) of salicylicacid and 0.5 mole of phosphorus trichloride were refluxed in 20 mls. ofchlorobenzene for three hours. Working up the reaction product asdescribed in Example 1 gave 1.06 gms. (35.1) of2'-a-naphthyloxysalicylanilide, M.P. -102 C. from 60-80 petroleum ether.

MIC 1-2 EXAMPLE 4 3,5-dichloro-2'-u-naphthyloxysalicylanilide Prepared,as described above in Example 1, from 2.0 gms. (0.0084 mole) of2-amino-u-naphthylether, 1.74 gms. (0.0084 mole) of3,5-dichloro-salicylic acid and 0.5 mls. of phosphorus trichloride.Recrystallisation of the product obtained gave 1.54 gms. (42.8%) of3,5-dichloro- 2-a-naphthyloxysalicylanilide, M.P. l67170 C. from analcohol-water mixture.

MIC 0.5-1.0

EXAMPLE 5 3,S-dichloro-2'-fl-naphthyloxysalicylanilide A solution of 2.0gms. (0.0084 mole) of Z-aminophenyl-,B-naphthylether, 1.74 gms. (0.0084mole) of 3,5- dichlorosalicylic acid and 0.5 m1. of phosphorustrichloride in 25 mls. of chlorobenzene was stirred and refluxed forthree hours. The hot reaction mixture was filtered, and the filtrateevaporated to one half of its original volume in a current of dry air.The precipitated solid was filtered, washed with 60-80 petroleum etherto give 2.9 gms. (85%) of 3,5-dichloro 2' 6 naphthyloxysalicylanilide,M.P. -191 C. from an alcohol-water mixture.

MIC 0.5-1.0

EXAMPLE 6 3 ,5 ,3 -trichloro-2'-fl-naphthyloxysalicylanilide A solutionof 1.5 gms. (0.005 mole) of 4-chloro-2- amino-,S-naphthylether, 1.03gms. (0.005 mole) 3,5-di- *Minimum Inhibitory Concentration againstStaph. aureus in parts per million.

chlorosalicylic acid and 0.25 ml. of phosphorus trichloride was refluxedin 20 mls. of chlorobenzene for three hours. Working up the reactionproduct as described in Example 5 gave 1.8 gms. (73.6%) of3,5,3-trichloro-2-fl-naphthyloxysalicylanilide, M.P. 209l C.

MIC 1.0

EXAMPLE 7 -chloro-2'-a-naphthyloxysalicylanilide A solution of 2.0 gms.(0.0084 mole) of Z-aminophenyl-a-naphthylether 1.45 gms. (0.0084 mole)of 5- chlorosalicylic acid and 0.5 ml. of phosphorus trichloride in mls.of chlorobenzene was refluxed for three hours. Working up the reactionproduct as described in Example 5 gave 0.85 gm. (25.6%) of5-chloro-2'-a-naphthyloxysalicylanilide, M.P. 184-6 C. from analcohol-water mixture.

MIC 0.1-0.5

EXAM PLE 8 3,4-dichloro-2'-,8-naphthyloxycarbanilide To a stirredsolution of 2 gms. (0.0084 mole) of 2- aminophenyl-a-naphthylether in 20mls. chloroform was added 1.58 gms. (0.0084 mole) of3,4-dichlorophenylisocyanate, and the mixture stirred for 3 /2 hours.The chloroform was removed under reduced pressure, and the crude productwashed twice with 60-80 petroleum ether. Recrystallisation of this solidfrom an alcohol-water mixture gave 1.948 gms. (54.4%) of3,4-dichloro-2-u-naphthyloxy-carbanilide, M.P. 18l-3 C.

MIC 1-2 EXAMPLE 1O 3,3',4-trichloro-2'-fl-naphthyloxycarbanilide To 1gm. (0.0037 mole) of 4-chloro-2-aminophenyl-B- naphthylether in 15 mls.chloroform was added 0.7 gm.

(0.0037 mole) of 3,4-dichlorophenylisocyanate, and the reaction mixturetreated as in Example 8. Recrystallisation of the crude product from analcohol-water mixture gave 0.88 gm. (51.8%)3,3,4-trichloro-2-fi-naphthyloxycarbanilide, M.P. 189-91.

MIC l-2 By way of comparison, the MIC of salicylanilide is 50.

What is claimed is:

l. A naphthyloxy-substituted salicylanilide selected from the groupconsisting of 2-(alphaenaphthyloxy)-.salicylanilides and 2'-(betanaphthyloxy) salicylanilides and wherein from 0 to 3 of the 3, 4, 5, 6,3, 4, 5' and 6 positions of the salicylanilide may have attached theretoa chlorine atom instead of a hydrogen atom.

2. A naphthyloxy-substituted salicylanilide according to claim 1 whichis 2'-(alpha-naphthyloxy)-salicylanilide.

3. A naphthyloxy-substituted salicylanilide according to claim 1 whichis 2'-(beta-naphthyloxy)-salicylanilide.

4. A naphthyloxy-substituted salicylanilide according to claim 1 whichis substituted with 1 to 3 chlorine atoms.

5. A naphthyloxy-substituted salicylanilide according to claim 4 whichis 5-chloro-2'-(beta-naphthyloxy)-salicylanilide.

6. A naphthyloxy-substituted salicylanilide according to claim 4 whichis 3,5-dichloro-2'-(alpha naphthyloxy)- salicylanilide.

7. A naphthyloxy-substituted salicylanilide according to claim 4 whichis 3,5-dichloro-2'-('beta-naphthyloxy)-salicylanilide.

8. A naphthyloxy-substituted salicylanilide according to claim 4 whichis 3,5-3-trichl0ro-2'-(beta naphthyloxy)- salicylanilide.

9. A naphthyloxy-substituted salicylanilide according to claim 4 whichis 5-chloro-2-(alpha-naphthyloxy)-salicylanilide.

References Cited UNITED STATES PATENTS 3,549,704 12/1970 Katerberg et a1260-559 HENRY R. JILES, Primary Examiner H. I. MONATZ, AssistantExaminer U.S. Cl. X.R.

